Cocaine dependence remains an alarming health issue, and an important research imperative is the development of effective treatment medications. The behavioral effects of cocaine are modulated by pharmacological manipulation of the 5-HT system and we have demonstrated that two 5-HT receptors, the 5-HT2A receptor (5-HT2AR) and the 5-HT2CR, exert excitatory and inhibitory control, respectively, over the behavioral effects of cocaine in an almost perfectly oppositional manner in rats. We propose that the ventral tegmental area (VTA) is one essential site for the 5-HT2R influence over the rewarding and reinforcing effects of cocaine. The VTA is comprised of dopamine (DA) and gamma- aminobutyric (GABA) neurons that form circuits with limbic and cortical nuclei that play a vital role in the in vivo effects of cocaine. The long term goals of the proposed multidisciplinary project are to elucidate the roles played by the 5-HT2AR and 5-HT2CR in the rewarding and reinforcing effects of cocaine including determination of the anatomical and functional heterogeneity of 5-HT2R regulation of the VTA. These goals will be addressed in four specific aims that have evolved conceptually from the progress reported for this project. Specific Aim 1 will test the hypothesis that an oppositional influence of the 5-HT2AR and 5-HT2CR is important in the rewarding and reinforcing effects of cocaine as measured by the conditioned place preference and self-administration assays, thus extending our current observations to models thought to reflect mechanisms underlying addiction. We will investigate the macrocircuitry and heterogeneity of the VTA that is involved in the oppositional control of behavior by 5-HT2AR (Specific Aim 2) and 5-HT2CR (Specific Aim 3) by employing immunohistochemical, pharmacological, intracranial microinjection, and behavioral techniques to map receptor localization and the loci of actions within the VTA that underlie specific aspects of the rewarding and reinforcing effects of cocaine. In Specific Aim 4, we will utilize virally-mediated gene transfer methodology to stably manipulate the abundance of 5-HT2AR and 5-HT2CR in the VTA to address several specific hypotheses concerning the role of these receptors in the rewarding and reinforcing effects of cocaine and to functionally validate circuitry information gleaned from Aims 2 and 3. Knowledge of the heterogeneity of the 5-HT2AR and 5-HT2CR to control the rewarding and reinforcing effects of cocaine and the role of VTA in these processes will reveal cellular targets that can be exploited in the development of new and effective pharmacotherapy not only for addiction to the abused drug cocaine, but also in other disorders characterized bv dysfunction within mesocorticolimbic circuits.